New data and an old puzzle: the negative association between schizophrenia and rheumatoid arthritis

2015

Lee, Sang Hong

Byrne, Enda M

Karlsson, Robert

Mattheisen, Manuel

Mattingsdal, Morten

McCarroll, Steven A

Medeiros, Helena

Melle, Ingrid

Milanova, Vihra

Myin-Germeys, Inez

Neale, Benjamin M

Ophoff, Roel A

Owen, Michael J

Mantzioris, Vasilis X

Pimm, Jonathan

Purcell, Shaun M

Puri, Vinay

Quested, Digby J

Rossin, Lizzy

Ruderfer, Douglas

Sanders, Alan R

Shi, Jianxin

Sklar, Pamela

St Clair, David

McGrath, John J

Stroup, T Scott

Van Os, Jim

Visscher, Peter M

Wiersma, Durk

Zammit, Stanley

Bridges, S Louis

Choi, Hyon K

Coenen, Marieke J H

de Vries, Niek

Dieude, Philippe

Mehta, Divya

Greenberg, Jeffrey D

Huizinga, Tom W J

Padyukov, Leonid

Siminovitch, Katherine A

Tak, Paul P

Worthington, Jane

De Jager, Philip L

Denny, Joshua C

Gregersen, Peter K

Klareskog, Lars

Stahl, Eli A

Mariette, Xavier

Plenge, Robert M

van Laar, Mart

van Riel, Piet

Zhao, Qiongyi

Kendler, Kenneth S

Sullivan, Patrick F

Price, Alkes L

O’Donovan, Michael

Hultman, Christina M

Okada, Yukinori

Mowry, Bryan J

Raychaudhuri, Soumya

Wray, Naomi R

Byerley, William

Cahn, Wiepke

Cantor, Rita M

Cichon, Sven

Cormican, Paul

Curtis, David

Kahler, Anna

Djurovic, Srdjan

Escott-Price, Valentina

Gejman, Pablo V

Georgieva, Lyudmila

Giegling, Ina

Hansen, Thomas F

Ingason, Andres

Kim, Yunjung

Konte, Bettina

Lee, Phil H

Vinkhuyzen, Anna A E

McIntosh, Andrew

McQuillin, Andrew

Morris, Derek W

Nothen, Markus M

O'Dushlaine, Colm

Olincy, Ann

Olsen, Line

Pato, Carlos N

Pato, Michele T

Pickard, Benjamin S

Ripke, Stephan

Posthuma, Danielle

Rasmussen, Henrik B

Rietschel, Marcella

Rujescu, Dan

Schulze, Thomas G

Silverman, Jeremy M

Thirumalai, Srinivasa

Werge, Thomas

Agartz, Ingrid

Amin, Farooq

Andreassen, Ole A

Azevedo, Maria H

Bass, Nicholas

Black, Donald W

Blackwood, Douglas H R

Bruggeman, Richard

Buccola, Nancy G

Choudhury, Khalid

Cloninger, C Robert

Corvin, Aiden

Craddock, Nicholas

Frisell, Thomas

Daly, Mark J

Datta, Susmita

Donohoe, Gary J

Duan, Jubao

Dudbridge, Frank

Fanous, Ayman

Freedman, Robert

Freimer, Nelson B

Friedl, Marion

Gill, Michael

Gusev, Alexander

Gurling, Hugh

De Haan, Lieuwe

Hamshere, Marian L

Hartmann, Annette M

Holmans, Peter A

Kahn, Rene S

Keller, Matthew C

Kenny, Elaine

Kirov, George K

Krabbendam, Lydia

Hu, Xinli

Krasucki, Robert

Lawrence, Jacob

Lencz, Todd

Levinson, Douglas F

Lieberman, Jeffrey A

Lin, Dan-Yu

Linszen, Don H

Magnusson, Patrik K E

Maier, Wolfgang

Malhotra, Anil K

Journal Article

en

Publication

Oxford University Press

United Kingdom

10.1093/ije/dyv136

une:18957

Background: A long-standing epidemiological puzzle is the reduced rate of rheumatoid arthritis (RA) in those with schizophrenia (SZ) and vice versa. Traditional epidemiological approaches to determine if this negative association is underpinned by genetic factors would test for reduced rates of one disorder in relatives of the other, but sufficiently powered data sets are difficult to achieve. The genomics era presents an alternative paradigm for investigating the genetic relationship between two uncommon disorders. Methods: We use genome-wide common single nucleotide polymorphism (SNP) data from independently collected SZ and RA case-control cohorts to estimate the SNP correlation between the disorders. We test a genotype X environment (GxE) hypothesis for SZ with environment defined as winter- vs summer-born. Results: We estimate a small but significant negative SNP-genetic correlation between SZ and RA (−0.046, s.e. 0.026, P =0.036). The negative correlation was stronger for the SNP set attributed to coding or regulatory regions (−0.174, s.e. 0.071, P =0.0075). Our analyses led us to hypothesize a gene-environment interaction for SZ in the form of immune challenge. We used month of birth as a proxy for environmental immune challenge and estimated the genetic correlation between winter-born and non-winter born SZ to be significantly less than 1 for coding/regulatory region SNPs (0.56, s.e. 0.14, P =0.00090). Conclusions: Our results are consistent with epidemiological observations of a negative relationship between SZ and RA reflecting, at least in part, genetic factors. Results of the month of birth analysis are consistent with pleiotropic effects of genetic variants dependent on environmental context.

link

International Journal of Epidemiology, 44(5), p. 1706-1721

1464-3685

0300-5771

1706

1721